This K99/R00 application is for Dr Tara Spires-Jones, an instructor at Massachusetts General Hospital / Harvard Medical School. Dr Spires-Jones completed her graduate work at the University of Oxford on a British Marshall Scholarship and National Science Foundation fellowship. In 2004, she moved to the Alzheimer's Research Unit at the Massachusetts General Hospital as a postdoctoral fellow under Prof Bradley T Hyman. Here she received postdoctoral training completing research projects related to synaptic loss in Alzheimer's disease mouse models, and was promoted in 2006 to Instructor. Dr Spires-Jones has successfully applied for several small foundation grants and has gained valuable teaching and supervisory experience, which she plans to expand with the career development award. Massachusetts General Hospital is an excellent center of research in the field of neurodegenerative disease. Prof Hyman, the mentor for the proposed award, is head of the Alzheimer's disease Research Center and one of the top scientists in Alzheimer's research. The institution has shown a strong commitment to the candidate's career development and is interested in recruiting Dr Spires-Jones to stay for the independent phase of the award as a tenure-track independent investigator. Dr Spires-Jones' future plans include pursuing an academic career as an independent research scientist in the field of plasticity during aging and neurodegenerative diseases. During normal aging, some synapses are lost, and learning and remembering things often becomes more difficult. These processes are more dramatic in Alzheimer's disease (AD), where synapse loss correlates strongly with cognitive decline. The proposed project will investigate the causes of synapse loss in Alzheimer model mice and further examine the role of aging and Alzheimer pathology on structural plasticity. The mentored phase of the proposed project will test the hypothesis that plaque-associated synapse loss in AD model mice is caused by oligomeric amyloid beta. These experiments will make use of biochemical techniques and a new staining and imaging technology called array tomography to localize amyloid beta at the postsynaptic density as well as in vivo multiphoton imaging to observe neuronal recovery after immunotherapy treatment. This work will then build to test the hypothesis that structural plasticity in response to altered somatosensory input and environmental enrichment will be decreased in AD model mice due to oligomeric amyloid beta surrounding plaques. Finally, in the independent phase of the award, the experience and knowledge gained form AD models will be used to expand the studies to determine the causes of synapse dysfunction and loss during normal aging. These experiments will be important to determine the causes of synapse loss during AD and will indicate whether environmental changes such as exercise and cognitively stimulating activities may be beneficial to promote healthy aging and to delay cognitive decline in Alzheimer's disease.